JPH06511155A - ギャップを有する2′修飾オリゴヌクレオチド - Google Patents
ギャップを有する2′修飾オリゴヌクレオチドInfo
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- JPH06511155A JPH06511155A JP5511953A JP51195393A JPH06511155A JP H06511155 A JPH06511155 A JP H06511155A JP 5511953 A JP5511953 A JP 5511953A JP 51195393 A JP51195393 A JP 51195393A JP H06511155 A JPH06511155 A JP H06511155A
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Abstract
Description
Claims (48)
- 1.核酸鎖に特異的にハイブリッド形成しうるヌクレオチド単位の配列を含むオ リゴヌクレオチドであって: 少なくとも1個のヌクレオチド単位が該オリゴヌクレオチドのヌクレアーゼ耐性 を高めるために官能化されており;少なくとも1個のヌクレオチド単位が上記の 核酸鎖への該オリゴヌクレオチドの結合親和性を高める置換基を保有し;かつ複 数のヌクレオチド単位が2′−デオキシ−erythro−ペントフラノシル糖 部分を有し、これらの2′−デオキシ−erythro−ペントフラノシルヌク レオチド単位がヌクレオチド単位の配列内に連続して位置するオリゴヌクレオチ ド。
- 2.結合親和性を高めるための置換基が2′−置換基からなる、請求の範囲第1 項に記載のオリゴヌクレオチド。
- 3.2′−置換基がフルオロ、C1−C9アルコキシ、C1−C9アミノアルコ キシ、アリルオキシ、イミダゾールアルコキシおよびポリ(エチレングリコール )である、請求の範囲第2項に記載のオリゴヌクレオチド。
- 4.ヌクレオチド単位がそれぞれホスホロチオエートまたはホスホロジチオエー トーヌクレオチドである、請求の範囲第1項に記載のオリゴヌクレオチド。
- 5.オリゴヌクレオチドの3′末端ヌクレオチド単位が該ヌクレオチド単位の2 ′または3′位のうち少なくとも−方にヌクレアーゼ耐性修飾基を含む、請求の 範囲第1項に記載のオリゴヌクレオチド。
- 6.複数のヌクレオチド単位が核酸鎖へのオリゴヌクレオチドの結合親和性を高 める置換基を保有し、これらの置換基保有ヌクレオチドが第1ヌクレオチド単位 サブ配列および第2ヌクレオチド単位サブ配列に分けられ;かつ複数の2′−デ オキシ−erythro−ペントフラノシル−ヌクレオチド単位が、ヌクレオチ ド単位の配列内で第1ヌクレオチド単位サブ配列と第2ヌクレオチド単位サブ配 列の間に位置する、請求の範囲第1項に記載のオリゴヌクレオチド。
- 7.複数のヌクレオチド単位が相補的核酸鎖へのオリゴヌクレオチドの結合親和 性を高める置換基を保有し;かつ 置換基を保有するこれらのヌクレオチドの少なくとも−部が該オリゴヌクレオチ ドの3′末端または5′末端のうち−方に連続して位置する、請求の範囲第1項 に記載のオリゴヌクレオチド。
- 8.少なくとも5個のヌクレオチド単位が2′−デオキシ−erythro−ペ ントフラノシル糖部分を有し、これら少なくとも5個の2′−デオキシ−ery thro−ペントフラノシルヌクレオチド単位がヌクレオチド単位の配列内に連 続して位置する、請求の範囲第1項に記載のオリゴヌクレオチド。
- 9.1−約8個のヌクレオチド単位が相補鎖へのオリゴヌクレオチドの結合親和 性を高める置換基を保有し、置換基を保有するこれらのヌクレオチド単位がヌク レオチド単位の配列内に連続して位置する、請求の範囲第1項に記載のオリゴヌ クレオチド。
- 10.1−約8個のヌクレオチド単位が相補鎖へのオリゴヌクレオチドの結合親 和性を高める置換基を保有し、置換基を保有するこれらのヌクレオチド単位がヌ クレオチド単位の配列内に連続して位置し;かつ少なくとも5個のヌクレオチド 単位が2′−デオキシ−erythro−ペントフラノシル糖部分を有し、これ ら少なくとも5個の2′−デオキシ−erythro−ペントフラノシル−ヌク レオチド単位がヌクレオチド単位の配列内に連続して位置する、 請求の範囲第1項に記載のオリゴヌクレオチド。
- 11.核酸鎖に特異的にハイブリッド形成しうるホスホロチオエートヌクレオチ ドの配列を含むオリゴヌクレオチドであって:複数のヌクレオチドが上記の核酸 鎖への該オリゴヌクレオチドの結合親和性を高める置換基を保有し;かつ 複数のヌクレオチドが2′−デオキシ−erythro−ペントフラノシル糖部 分を有する オリゴヌクレオチド。
- 12.結合親和性を高めるための置換基が2′−置換基からなる、請求の範囲第 11項に記載のオリゴヌクレオチド。
- 13.2′−置換基がフルオロ、C1−C9アルコキシ、C1−C9アミノアル コキシまたはアリルオキシである、請求の範囲第12項に記載のオリゴヌクレオ チド。
- 14.さらに複数の、2′−置換基を保有するヌクレオチド;オリゴヌクレオチ ド内で2′−置換基を保有するヌクレオチド基の間に位置する2′−デオキシ− erythro−ペントフラノシルヌクレオチドを含む、請求の範囲第12項に 記載のオリゴヌクレオチド。
- 15.置換基を保有するヌクレオチドがオリゴヌクレオチドの3′末端または5 ′末端のうち−方に位置する、請求の範囲第11項に記載のオリゴヌクレオチド 。
- 16.核酸鎖に特異的にハイブリッド形成しうるホスホロチオエートヌクレオチ ドの配列を含むオリゴヌクレオチドであって:第1部分のヌクレオチドが2′− デオキシ−2′−フルオロ、2′−メトキシ、2′−エトキシ、2′−プロポキ シ、2′−アミノプロポキシ、または2′−アリルオキシ−ペントフラノシル糖 部分を有し;かつ他の部分のヌクレオチドが2′−デオキシ−erythro− ペントフラノシル糖部分を含む オリゴヌクレオチド。
- 17.第1部分のヌクレオチドがオリゴヌクレオチドの3′末端または5′末端 のいずれかに位置する、請求の範囲第16項に記載のオリゴヌクレオチド。
- 18.2′−デオキシ−2′−フルオロ、2′−メトキシ、2′−エトキシ、2 ′−プロポキシ、2′−アミノプロポキシ、または2′−アリルオキシ−ペント フラノシル糖部分を有する追加部分のヌクレオチドを含み;かつ他の部分のヌク レオチドがヌクレオチド内で第1部分のヌクレオチドと追加部分のヌクレオチド の間に位置する、請求の範囲第17項に記載のオリゴヌクレオチド。
- 19.望ましくない蛋白質産生を特色とする疾病を伴う生物の治療方法であって 、該蛋白質をコードする核酸鎖に特異的にハイブリッド形成しうるヌクレオチド の配列を有し、少なくとも1個のヌクレオチドがオリゴヌクレオチドのヌクレア ーゼ耐性を高めるために官能化され、複数のヌクレオチドが上記の核酸鎖に対す るオリゴヌクレオチドの結合親和性を高めるためにそれに配置された置換基を有 し、かつ複数のヌクレオチドが2′−デオキシ−erythro−ペントフラノ シル糖部分を有するオリゴヌクレオチドと、該生物を接触させることを含む方法 。
- 20.ヌクレオチドがそれぞれホスホロチオエートーヌクレオチドである、請求 の範囲第19項に記載の方法。
- 21.置換基が2′−置換基である、請求の範囲第19項に記載の方法。
- 22.2′−置換基がフルオロ、アルコキシ、アミノアルコキシまたはアリルオ キシである、請求の範囲第21項に記載の方法。
- 23.薬剤学的に有効な量の、核酸鎖に特異的にハイブリッド形成しうるヌクレ オチドの配列を有し、少なくとも1個のヌクレオチドがオリゴヌクレオチドのヌ クレアーゼ耐性を高めるために官能化され、複数のヌクレオチドが相補的核酸鎖 に対するオリゴヌクレオチドの結合親和性を高めるためにそれに配置された置換 基を有し、複数のヌクレオチドが2′−デオキシ−erythro−ペントフラ ノシル糖部分を有するオリゴヌクレオチド;および薬剤学的に許容しうる希釈剤 またはキャリヤーを含む薬剤組成物。
- 24.配列特異性核酸のインビトロ修飾方法であって、核酸鎖に特異的にハイブ リッド形成しうるヌクレオチドの配列を有し、少なくとも1個のヌクレオチドが オリゴヌクレオチドのヌクレアーゼ耐性を高めるために官能化され、複数のヌク レオチドが相補的核酸鎖に対するオリゴヌクレオチドの結合親和性を高めるため にそれに配置された置換基を有し、かつ複数のヌクレオチドが2′−デオキシ− erythro−ペントフラノシル糖部分を有するオリゴヌクレオチドと、RN aseHおよび上記核酸を含有する被験溶液とを接触させることを含む方法。
- 25.生物においてハイブリッド形成およびRNaseH活性化を同時に増大さ せる方法であって、相補的核酸鎖に特異的にハイブリッド形成しうるヌクレオチ ドの配列を有し、少なくとも1個のヌクレオチドがオリゴヌクレオチドのヌクレ アーゼ耐性を高めるために官能化され、複数のヌクレオチドが相補的核酸鎖に対 するオリゴヌクレオチドの結合親和性を高めるためにそれに配置された置換基を 有し、かつ複数のヌクレオチドが2′−デオキシ−erythro−ペントフラ ノシル糖部分を有するオリゴヌクレオチドと、該生物を接触させることを含む方 法。
- 26.相補的核酸にハイブリッド形成しうる配列で共有結合により結合した複数 のヌクレオシドを含む高分子であって:ヌクレオシドがα−ヌクレオシド、2′ −デオキシ−erythro−ペントフラノシルβ−ヌクレオシドを含むβ−ヌ クレオシド、4′−チオヌクレオシド、および炭素環式ヌクレオシドから選ばれ ;該結合が帯電リン結合、中性リン結合、または非リン結合から選ばれ;かつ 結合したヌクレオシドの配列が少なくとも2つのヌクレオシド領域を含み; その第1領域が、帯電および中性3′−5′リン結合により結合したα−ヌクレ オシド、帯電および中性2′−5′リン結合により結合したα−ヌクレオシド、 非リン結合により結合したα−ヌクレオシド、帯電および中性3′−5′リン結 合により結合した4′−チオヌクレオシド、帯電および中性2′−5′リン結合 により結合した4′−チオヌクレオシド、非リン結合により結合した4′−チオ ヌクレオシド、帯電および中性3′−5′リン結合により結合した炭素環式ヌク レオシド、帯電および中性2′−5′リン結合により結合した炭素環式ヌクレオ シド、非リン結合により結合した炭素環式ヌクレオシド、帯電および中性2′− 5′リン結合により結合したβ−ヌクレオシド、非リン結合により結合したβ− ヌクレオシドから選ばれるヌクレオシドを含み;かつその第2領域が、生理的p Hにおいて負の電荷をもつ帯電3′−5′リン結合により結合した2′−デオキ シ−erythro−ペントフラノシルβ−ヌクレオシドからなる 高分子。
- 27.第2領域が少なくとも3個の2′−デオキシ−erythro−ペントフ ラノシルβ−ヌクレオシドを含む、請求の範囲第26項に記載の高分子。
- 28.第2ヌクレオシド領域が第1ヌクレオシド領域と第3ヌクレオシド領域の 間に位置し、この第3ヌクレオシド領域が、帯電および中性3′−5′リン結合 により結合したα−ヌクレオシド、帯電および中性2′−5′リン結合により結 合したα−ヌクレオシド、非リン結合により結合したα−ヌクレオシド、帯電お よび中性3′−5′リン結合により結合した4′−チオヌクレオシド、帯電およ び中性2′−5′リン結合により結合した4′−チオヌクレオシド、非リン結合 により結合した4′−チオヌクレオシド、帯電および中性3′−5′リン結合に より結合した炭素環式ヌクレオシド、帯電および中性2′−5′リン結合により 結合した炭素環式ヌクレオシド、非リン結合により結合した炭素環式ヌクレオシ ド、帯電および中性2′−5′リン結合により結合したβ−ヌクレオシド、非リ ン結合により結合したβ−ヌクレオシドから選はれるヌクレオシドを含む、請求 の範囲第26項に記載の高分子。
- 29.帯電リン結合が、ホスホジエステル、ホスホロチオエート、ホスホロジチ オエート、ホスホロセレネートまたはホスホロジセレネート結合を含む、請求の 範囲第26項に記載の高分子。
- 30.帯電リン結合が、ホスホジエステルまたはホスホロチオエートである、請 求の範囲第26項に記載の高分子。
- 31.中性リン結合が、アルキルおよびアリールホスホネート、アルキルおよび アリールホスホロアミダイト、アルキルおよびアリールホスホトリエステル、ハ イドロジェンホスホネート、ならびにボラノホスフェート結合を含む、請求の範 囲第26項に記載の高分子。
- 32.非リン結合が、ペプチド結合、ヒドラジン結合、ヒドロキシアミン結合、 カルバメート結合、モルホリン結合、カーボネート結合、アミド結合、オキシメ チレンイミン結合、ヒドラジド結合、シリル結合、スルフィド結合、ジスルフィ ド結合、スルホン結合、スルホキシド結合、スルホネート結合、スルホンアミド 結合、ホルムアセタール結合、チオホルムアセタール結合、オキシム結合、およ びエチレングリコール結合を含む、請求の範囲第26項に記載の高分子。
- 33.第1ヌクレオシド領域が帯電または中性3′−5′リン結合により結合し たα−ヌクレオシド少なくとも2個を含む、請求の範囲第26項に記載の高分子 。
- 34.相補的核酸にハイブリッド形成しうる配列で共有結合により結合した複数 の単位を含む高分子であって: 該単位がヌクレオシドおよび核酸塩基から選ばれ;ヌクレオシドがα−ヌクレオ シド、2′−デオキシ−erythro−ペントフランシルβ−ヌクレオシドを 含むβ−ヌクレオシド、4′−チオヌクレオシド、および炭素環式ヌクレオシド から選ばれ;核酸塩基がプリン−9−イルおよびピリミジン−1−イル複素環式 塩基から選ばれ; 該結合が帯電3′−5′リン結合、中性3′−5′リン結合、帯電2′−5′リ ン結合、中性2′−5′リン結合、または非リン結合から選ばれ;かつ結合した 単位の配列が少なくとも2つの領域に分けられ:その第1領域が、非リン結合に より結合した核酸塩基、および非糖−締結基を介してリン酸結合に結合した核酸 塩基、ならびに帯電および中性3′−5′リン結合により待合したα−ヌクレオ シド;帯電および中性2′−5′リン結合により結合したα−ヌクレオシド;非 リン結合により結合したα−ヌクレオシド;帯電および中性3′−5′リン結合 により結合した4′−チオヌクレオシド;帯電および中性2′−5′リン結合に より結合した4′−チオヌクレオシド;非リン結合により結合した4′−チオヌ クレオシド;帯電および中性3′−5′リン結合により結合した炭素環式ヌクレ オシド;帯電および中性2′−5′リン結合により結合した炭素環式ヌクレオシ ド;非リン結合により結合した炭素環式ヌクレオシド;帯電および中性2′−5 ′結合により結合したβ−ヌクレオシド;非リン結合により結合したβ−ヌクレ オシドから選ばれるヌクレオシドを含み;かつ その第2領域が、生理的pHにおいて負の電荷をもつ帯電3′−5′リン結合に より結合した2′−デオキシ−erythro−ペントフラノシルβ−ヌクレオ シドを含む 高分子。
- 35.第1領域が、非リン結合により結合した核酸塩基少なくとも2個を含む、 請求の範囲第34項に記載の高分子。
- 36.非リン結合がペプチド結合である、請求の範囲第35項に記載の高分子。
- 37.第2領域が第1領域と第3領域の間に位置し、この第3領域が、非リン結 合により結合した核酸塩基、および非糖−締結部分を介してリン酸結合に結合し た核酸塩基、ならびに帯電および中性3′−5′リン結合により結合したα−ヌ クレオシド、帯電および中性2′−5′リン結合により結合したα−ヌクレオシ ド、非リン結合により結合したα−ヌクレオシド、帯電および中性3′−5′リ ン結合により結合した4′−チオヌクレオシド、帯電および中性2′−5′リン 結合により結合した4′−チオヌクレオシド、非リン結合により結合した4′− チオヌクレオシド、帯電および中性3′−5′リン結合により結合した炭素環式 ヌクレオシド、帯電および中性2′−5′リン結合により結合した炭素環式ヌク レオシド、非リン結合により結合した炭素環式ヌクレオシド、帯電および中性2 ′−5′リン結合により結合したβ−ヌクレオシド、非リン結合により結合した β−ヌクレオシドから選はれるヌクレオシドを含む、請求の範囲第35項に記載 の高分子。
- 38.核酸塩基がアデニン、グアニン、シトシン、ウラシル、チミン、キサンチ ン、ヒポキサンチン、2−アミノアデニン、6−メチルおよび他のアルキルアデ ニン、2−プロピルおよび他のアルキルアデニン、5−ハロウラシルおよびシト シン、6−アザウラシル、シトシンおよびチミン、5−ウラシル(プソイドウラ シル)、4−チオウラシル、8−ハロ、アミノ、チオール、チオールアルキル、 ヒドロキシルおよび他の8置換アデニンおよびグアニン、または5−トリフルオ ロメチルウラシルおよびシトシンから選はれる、請求の範囲第35項に記載の高 分子。
- 39.相補的核酸にハイブリッド形成しうる配列で共有結合により結合した複数 の単位を含む高分子であって: 該単位がヌクレオシドおよび核酸塩基から選はれ;ヌクレオシドがα−ヌクレオ シド、β−ヌクレオシド、4′−チオヌクレオシド、および炭素環式ヌクレオシ ドから選はれ;核酸塩基がプリン−9−イルおよびピリミジン−1−イル複素環 式塩基から選ばれ; 該結合が帯電リン結合、中性リン結合、または非リン結合から選ばれ;かつ 結合した単位の配列が少なくとも2つの領域に分けられ:その第1領域が、帯電 および中性3′−5′リン結合により結合したα−ヌクレオシド;帯電および中 性2′−5′リン結合により結合したα−ヌクレオシド;非リン結合により結合 したα−ヌクレオシド;帯電および中性3′−5′リン結合により結合した4′ −チオヌクレオシド,帯電および中性2′−5′リン結合により結合した4′− チオヌクレオシド;非リン結合により結合した4′−チオヌクレオシド;帯電お よび中性リン結合により結合した炭素環式ヌクレオシド;非リン結合により結合 した炭素環式ヌクレオシド;帯電および中性3′−5′リン結合により結合した β−ヌクレオシド;帯電および中性2′−5′結合により結合したβ−ヌクレオ シド;非リン結合により結合したβ−ヌクレオシドから選ばれるヌクレオシドを 含み:かつその第2領域が、非リン結合により結合した核酸塩基、および非糖− 締結部分を介してリン酸結合に結合した核酸塩基を含む高分子。
- 40.非リン酸結合がペプチド結合である、請求の範囲第38項に記載の高分子 。
- 41.複数の第1領域を含む、請求の範囲第38項に記載の高分子。
- 42.複数の第2領域を含む、請求の範囲第38項に記載の高分子。
- 43.複数の第1領域を含む、請求の範囲第41項に記載の高分子。
- 44.望ましくない蛋白質産生を特色とする疾病を伴う生物の治療方法であって 、該生物を請求の範囲第34項に記載の化合物と接触させることを含む方法。
- 45.薬剤学的に有効な量の請求の範囲第34項に記載の化合物、および薬剤学 的に許容しうる希釈剤またはキャリヤーを含む薬剤組成物。
- 46.配列特異性核酸のインビトロ修飾方法であって、RNaseHおよび上記 核酸を含有する被験溶液を請求の範囲第34項に記載の化合物と接触させること を含む方法。
- 47.望ましくない蛋白質産生を特色とする疾病を伴う生物の治療方法であって 、該生物を請求の範囲第39項に記載の化合物と接触させることを含む方法。
- 48.薬剤学的に有効な量の請求の範囲第39項に記載の化合物、および薬剤学 的に許容しうる希釈剤またはキャリヤーを含む薬剤組成物。
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- 1992-12-23 KR KR1019940702197A patent/KR940703846A/ko not_active Application Discontinuation
- 1992-12-23 WO PCT/US1992/011339 patent/WO1993013121A1/en active IP Right Grant
- 1992-12-23 EP EP00202252A patent/EP1044987B1/en not_active Expired - Lifetime
- 1992-12-23 AU AU34275/93A patent/AU669353B2/en not_active Expired
- 1992-12-23 DE DE69233599T patent/DE69233599T2/de not_active Expired - Lifetime
- 1992-12-23 DE DE69232032T patent/DE69232032T3/de not_active Expired - Lifetime
- 1992-12-23 AT AT06075176T patent/ATE515510T1/de not_active IP Right Cessation
- 1992-12-23 AT AT93902851T patent/ATE204879T1/de not_active IP Right Cessation
- 1992-12-23 CA CA002126691A patent/CA2126691C/en not_active Expired - Lifetime
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1999
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2000
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2001
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2003
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